Alzheimer's disease (AD) is a common neurodegenerative disorder affecting more than 3 million people in the United States. AD etiology is only partially understood. Four genes have been implicated in the inheritance of AD and additional genes remain to be identified. Recently, we and others studying frontotemporal dementia (FTD), found causative mutations in the gene encoding tau. Tau is the main protein of neurofibrillary tangles (NFT's) that are found in both AD and FTD. Other variants of tau pathology are also found in FTD (e.g glial fibrillary tangles). The FTD mutations demonstrate that genetic alterations in tau cause both neurodegeneration and tau pathology, that in some cases closely parallels the changes observed in AD. Thus, tau appears to be an active participant in neurodegenerative events and tau pathology is not just a secondary consequence of AD changes. Different tau mutations cause FTD by different mechanisms; in some cases, the biochemical properties of tau are altered while for other mutations, splicing of exon 10 appears to be altered. Mutations that affect splicing appear to act by 3 mechanisms; some affect the 5'splice site of exon 10, others alter exon splicing enhancer (ESE) regulatory elements, and at least one alters an exon splicing silencer. One goal of this proposal is to understand how the tau gene is regulated in normal and disease cells. First, the genomic sequence of the mouse and human tau gene will be determined and compared to identify conserved non-repeat sequences. Conserved regions are potential cis-acting regulatory elements. Second, the role of these conserved sequences in the regulation of normal splicing will be determined. Third, the mechanism by which polymorphisms and FTD mutations affect this splicing will be determined. We have identified over 30 tau polymorphisms in normal subjects and many of these are in potential regulatory sequences. A fourth goal is to evaluate the role of tau variants in AD. AD subjects will be screened for causative mutations as well as mutations that affect progression. A fifth goal is to refine the location of additional AD loci using Monte Carlo simulation methods for analysis of family data.